Modulation of cytochrome P450 metabolism and transport across intestinal epithelial barrier by ginger biophenolics

PLoS One. 2014 Sep 24;9(9):e108386. doi: 10.1371/journal.pone.0108386. eCollection 2014.

Abstract

Natural and complementary therapies in conjunction with mainstream cancer care are steadily gaining popularity. Ginger extract (GE) confers significant health-promoting benefits owing to complex additive and/or synergistic interactions between its bioactive constituents. Recently, we showed that preservation of natural "milieu" confers superior anticancer activity on GE over its constituent phytochemicals, 6-gingerol (6G), 8-gingerol (8 G), 10-gingerol (10 G) and 6-shogaol (6S), through enterohepatic recirculation. Here we further evaluate and compare the effects of GE and its major bioactive constituents on cytochrome P450 (CYP) enzyme activity in human liver microsomes by monitoring metabolites of CYP-specific substrates using LC/MS/MS detection methods. Our data demonstrate that individual gingerols are potent inhibitors of CYP isozymes, whereas GE exhibits a much higher half-maximal inhibition value, indicating no possible herb-drug interactions. However, GE's inhibition of CYP1A2 and CYP2C8 reflects additive interactions among the constituents. In addition, studies performed to evaluate transporter-mediated intestinal efflux using Caco-2 cells revealed that GE and its phenolics are not substrates of P-glycoprotein (Pgp). Intriguingly, however, 10 G and 6S were not detected in the receiver compartment, indicating possible biotransformation across the Caco-2 monolayer. These data strengthen the notion that an interplay of complex interactions among ginger phytochemicals when fed as whole extract dictates its bioactivity highlighting the importance of consuming whole foods over single agents. Our study substantiates the need for an in-depth analysis of hepatic biotransformation events and distribution profiles of GE and its active phenolics for the design of safe regimens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism
  • Fatty Alcohols / pharmacology
  • Gene Expression Regulation / drug effects
  • Ginger / chemistry*
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology*

Substances

  • Catechols
  • Cytochrome P-450 Enzyme Inhibitors
  • Fatty Alcohols
  • Plant Extracts
  • shogaol
  • Cytochrome P-450 Enzyme System
  • gingerol
  • 8-gingerol